System for delivering potassium chloride with enhanced bioacceptability

ABSTRACT

A composition of matter comprising a drug, a neutral hydrogel and an ionic hydrogel. The composition can be administered from a delivery system to a biological receptor over time.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.06/827,027 filed Feb. 7, 1986 now U.S. Pat. No. 4,729,957 whichapplication is assigned to ALZA Corporation and is incorporated hereinby reference and benefit is claimed of its filing date.

FIELD OF THE INVENTION

This invention pertains to a delivery system for delivering a drug withenhanced bioacceptability. More particularly, the invention concerns adelivery system for delivering a drug with a concomitant lessening ofthe incidence of adverse effects of the drug on the biologicalenvironment. The invention relates also to a composition of mattercomprising a drug, and to a method for using the dispensing system.

BACKGROUND OF THE INVENTION

There are many beneficial drugs known to medicine, veterinary andpharmacy that are administered for producing a beneficial effect thatoften have a serious shortcoming associated with their use. For example,the electrolyte drug potassium chloride is the pharmaceuticallyacceptable salt most frequently used when the benefit of the potassiumcation is desired for its indicated therapeutic effect. Potassiumchloride is used when hypokalemia exists, as a treatment with certaindiuretics, in steroid therapy, and for relieving the symptoms associatedwith Menier's disease. However, serious shortcomings are associated withits use, mainly potassium chloride is an irritant of gastrointestinalmucosa, and its use often leads to bowel lesions. Another important drugthat possesses similar shortcomings is aspirin. Aspirin, oracetylsalicylic acid, is used widely as an antipyretic and as ananalgesic in a variety of medical conditions. Aspirin is a very valuabledrug; however, the use of this drug in conventional dosage forms oftenis accompanied by gastrointestinal irritation. Another drug whoseusefulness is compromised by unwanted effects is indomethacin.Indomethacin exhibits both analgesic and anti-inflammatory propertiesand it is used mostly for the treatment of rheumatoid arthritis. Themost frequent unwanted actions associated with dosage forms containingthis drug are gastrointestinal mucosal disturbances similar to thosementioned immediately above.

Other drugs, such as the nonsteroidal, anti-inflammatory,pharmaceutically acceptable salts of ibuprofen, diclofenac, naproxen,fenoprofen, and the like, are widely used for the treatment ofinflammatory conditions, but they also suffer from the disadvantage thatthey can cause irritation of the mucosal lining of the digestive tract.Then, too, the widely used antiscurvy vitamin, ascorbic acid, is knownto elicit a similar irritation in warm-blooded animals, includinghumans. In many instances the irritation occurs as a result of anirritant producing drug being presented in a concentrated dosage formdirectly to the lining of the digestive tract, prior to diluting thedrug with digestive fluids.

The prior art has provided novel therapeutic systems manufactured in theform of osmotic devices for the precision administration of drugs atcontrolled delivery patterns over extended operational delivery times.These unique systems are disclosed in U.S. Pat. Nos. 3,845,770 and3,916,899, both issued to patentees Theeuwes and Higuchi. The systemsdisclosed in these patents comprise a semipermeable wall that surroundsa compartment containing a drug that is dispensed through at least oneexit passageway in the wall. The dispensing system disclosed by Theeuwesand Highuchi represent an outstanding and pioneering advancement in thedelivery art, and they are extraordinarily effective for delivering allkinds of drugs in the form of saturated solutions. While these systemsare useful for dispensing innumerable drugs to a biological environmentof use, there is an occasional instance where an unexpected advancementis needed in these systems for dispensing potentially irritating drugsof the type mentioned above. Thus, in light of this presentation, itwill be appreciated by those versed in the dispensing art that if apractical system is made available for dispensing such beneficial drugs,with a lessening of unwanted effects, such a dispensing system wouldhave a definite use and represent a valuable contribution to medicine,veterinary and the pharmaceutical arts.

OBJECTS OF THE INVENTION

Accordingly, in view of the above presentation, it is an immediateobject of this invention to provide a delivery system, a composition ofmatter, and a method for the controlled delivery of a drug, and whichsystem, composition and method represent an unexpected improvement inthe dispensing art and substantially overcome the disadvantages known tothe prior art.

Another object of the invention is to provide a delivery system fordelivering a beneficial drug that is prone to exhibit adverse effectswhich are attenuated by using the delivery system of this invention fordelivering it to a biological environment of use.

Another object of the invention is to provide a delivery system foradministering a drug accompanied by a lessening of mucosal tissueirritation.

Another object of the invention is to provide a delivery system foradministering a drug in a concentrical amount that is presented in lessthan a concentrated amount to a drug receiving biological surface of theenvironment of use.

Another object of the present invention is to provide an improvement indrug delivery by making available a delivery system for the ratecontrolled and continuous delivery of a beneficial drug in means forpresenting the drug in a diluted amount of the environment of use.

Another object of the present invention is to provide a drug deliverydevice for the administration of a drug comprising means for lesseningits direct contact with the tissues of the gastrointestinal tract forcorrespondingly decreasing the drug's ability to produce tissue injury,while concomitantly administering the drug in a therapeuticallyeffective dosage amount.

Another object of the invention is to provide a dispensing devicecomprising means for dispensing a drug for substantially preventing itfrom contacting directly the mucosal wall of the digestive tract wheresuch contact is detrimental prior to its dilution with digestive fluidpresent in the gastrointestinal tract.

Another object of the invention is to provide a delivery device thatenables the administration of drug in the gastrointestinal tract withoutpermitting contact of undissolved drug with the lining of thegastrointestinal tract before its in vivo dilution with gastrointestinalfluid.

Another object of the present invention is to provide a dispensingdevice for delivering a beneficial drug comprising means forcontinuously diminishing the concentration of a drug presented to thegastrointestinal tract for topical and systemic use.

Other objects, features and advantages of the invention will be moreapparent to those versed to the dispensing art from the followingdetailed specification taken in conjunction with the drawing figures andthe accompanying claims.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings, which are not drawn to scale, but are set forth toillustrate various embodiments of the invention, the drawing figures areas follows:

FIG. 1 is a view of a dispensing device designed for orallyadministering a beneficial drug to the gastrointestinal tract;

FIG. 2 is a opened view of the delivery system of FIG. 1 forillustrating the internal structure of the delivery system;

FIG. 3 is an opened view of the delivery system of FIG. 1 forillustrating the multiplicity of components housed in the compartment ofthe delivery system;

FIG. 4 is an opened view of a delivery system provided for dispensing adrug in a body passageway;

FIG. 5 is an opened view of a delivery system designed for use as a bodyimplant;

FIG. 6 is a graph indicating viscosity measurements in the compartmentof a device.

DETAILED DESCRIPTION OF THE DRAWINGS

Turning now to the drawing figures in detail, which drawing figures areexamples of delivery devices provided by the invention, and whichdrawing figures are not to be construed as limiting the invention, oneexample of a dispensing device is seen in FIG. 1 identified by thenumeral 10. In FIG. 1, dispensing device 10 comprises a body means 11comprising a wall means 12 for surrounding and forming an internalcompartment, not seen in FIG. 1, and at least one exit means 13 forconnecting the exterior of device 10 with the interior of device 10.

In FIG. 2, an osmotic device 10 is seen in opened view with wall 12opened at 14. In FIG. 2, dispensing device 10 comprises body member 11,wall 12 and internal compartment 15. Wall 12 of device 10 comprises anontoxic polymeric composition that is totally, or in at least a part,permeable to the passage of an external fluid, and it is substantiallyimpermeable to the passage of a beneficial drug formulation 16 presentin compartment 15. The polymeric composition comprising wall means 12 isinert and it maintains its physical and chemical integrity during thedispensing life of device 10. The phrase, "physical and chemicalintegrity" denotes wall means 12 does not lose its structure and it doesnot change during the dispensing life of device 10.

Internal compartment 15 houses a dispensable composition comprising abeneficial drug formulation 16, identified by dots, which drugformulation is releasably blended with a hydrogel carrier means 17,identified by dashes. Beneficial drug formulation 16 comprises a drugthat can be from insoluble to very soluble in fluid that passes throughwall means 12 into compartment 15. Beneficial drug formulation 16 incompartment 15 comprises, in a presently preferred embodiment, a drugthat can irritate mucosal tissue, such as the mucosal tissues of thegastrointestinal tract. The drug causes irritation by directlycontacting the mucosal tissues generally in a saturated amount and priorto the drug undergoing dissolution, dissolving or dilution by fluidpresent in an animal body, such as fluid present in the gastrointestinaltract. The hydrogel carrier is (1) a means for substantially lesseningor substantially avoiding the incidence of irritation associated with adrug that produces irritation on tissue contact, (2) a means forsubstantially reducing the concentration of an irritating drugformulation dispensed by device 10 and presented to a mucosal receptorsite, and (3) a means for substantially lessening direct drug mucosalcontact and concomitantly lessening the degree of tissue irritationassociated with an irritant drug.

Hydrogel carrier means 17 comprises a hydrophilic polymer compositionthat is noncross-linked or lightly cross-linked and it possesses theability to form a dispensable formulation by homogeneously orheterogeneously blending with drug formulation 16. Hydrogel carriermeans 17 can optionally be described as a tissue contact reducing meansas it reduces direct contact of device 10, and direct contact of drugformulation 16 with a mucosal tissue. In operation, hydrogel meansabsorbs and/or imbibes fluid, expands and forms a dispensableformulation that is released from device 10 simultaneously transportingdrug formulation 16 therewith. On its release, carrier means 17 furtherexpands in the presence of gastrointestinal fluid, thereby reducingdirect drug contact of drug formulation 16 with the mucosal tissue. Drugformulation 16 on its controlled release from device 10 in theaccompanyment of hydrogel means 17, undergoes dissolution ingastrointestinal fluid by formulation 16 mixing with fluid and forming adiluted suspension, or formulation 16 dissolves in gastrointestinalfluid and forms a solution. In either instance, the combined operationsof the hydrogel means and the drug formulation fluid interactions,present a less irritating drug formulation to the mucosal tissue,thereby lessening the incidence of unwanted irritation.

FIG. 3 illustrates another embodiment provided by the invention. In FIG.3, dispensing device 10 is seen in opened section with wall 12 openedand peeled-back at 14. In FIG. 3, dispensing device 10 comprises bodymember 11, wall means 12, passageway 13 in wall 12 and internalcompartment 15. In FIG. 3, dispensing device 10 comprises more than onepassageway as seen by the presence of second exit passageway 18.Internal compartment 15 houses a dispensable composition comprising abeneficial drug formulation 16, and a blend of at least two hydrogelmeans 17 and 19. The two hydrogel means both exhibit the ability tointeract with fluid and swell to some equilibrium state. Hydrogel means17 in a preferred embodiment comprises a neutral hydrogel that can swelland expand in the presence of both drug formulation 16 and fluid imbibedinto compartment 15 for forming a dispensable carrier. The in situformed carrier transports drug formulation 16 and second hydrogel 19from compartment 15. The second hydrogel 19, in a preferred embodiment,comprises an ionic hydrogel that exhibits a smaller degree of swellingin the presence of drug formulation 16 and first hydrogel means 17 incompartment 15. In operation, on the concomitant release of drugformulation 16, first hydrogel means 17 and second hydrogel means 19from compartment 15, both means 17 and means 19 interact with fluid inthe gastrointestinal environment of use, swell and retain absorbed fluidwithin their respective hydrogel structural networks. Simultaneouslydrug formulation 16 released from compartment 15 undergoes furtherdissolution, or dissolving in fluid, thereby decreasing theconcentration of the suspension or solution formed in the environment ofuse. Through these combined integrated, reciprocal actions, mainly, (1)by the expansion of hydrogel means 17 and 19, the contact of drugformulation with mucosal tissue is reduced by forming a hydrogelinterface between drug formulation 16 and the in vivo tissue, and (2) bythe dissolution or dissolving of the drug formulation in the fluid andin the presence of the expanding hydrogels, the concentration of drug isdecreased in vivo, whereby the irritation of tissue is diminished overtime.

FIG. 4 illustrates another embodiment of dispensing device 10. In FIG.4, dispensing device 10 is designed, sized and shaped for placement inan animal body passageway such as a vagina or the ano-rectal canal.Device 10 in the depicted embodiment, comprises an elongatedcylindrical, self-sustaining shape with a rounded lead end 21, atrailing end 22, and a manually controlled string 23 for easily removingdevice 10 from a biological passageway. Device 10 of FIG. 4 issubstantially identical with device 10 as described above and itoperates in a like manner. Device 10 of FIG. 4 comprises body 11 andwall 12. Wall 12 comprises a semipermeable composition permeable to thepassage of fluid and substantially impermeable to the passage of drugformulation 16. Wall 12 surrounds, in part, a microporous wall 24.Microporous wall 24 is formed of a microporous polymer compositioncomprising at least one or a plurality of pores 25. Micropores 25 are anexit means for releasing drug formulation 16 from device 10. In thiscapacity, a plurality of micropores 25 function as a diffuser and as anadditional means for diffusing drug formulation 16 to the environment ofuse. Microporous-releasing wall 24 thereby further lessens the incidenceof irritation of the vaginal mucosal or ano-rectal mucosal tissues.

FIG. 5 illustrates another device of the invention. FIG. 5 depicts anosmotic device 10 shaped and adapted for use as an implant. Implantabledevice 10 possesses the structural features and operates in the mannerdescribed above.

While FIGS. 1 through 5 are illustrative of dispensing devices that canbe made according to the invention, it is to be understood these devicesare not to be construed as limiting the invention, as the devices cantake a wide variety of shapes, sizes and forms for delivering abeneficial drug to an environment of use. For example, the devicesinclude buccal, artificial gland, cervical, intrauterine, nasal,subcutaneous, dermal, and the like. The devices can be adapted foradministering a beneficial drug to animals, which term includeswarm-blooded mammals, humans, primates, household animals, sportanimals, farm animals and zoo animals. The devices can be adapted alsofor administering a drug in a therapeutically effective amount toavians, pisces and reptiles.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the practice of the invention, it has now been foundthat delivery device 10 can be manufactured with a wall formed ofmaterials that do not adversely affect the beneficial drug formulation,the hydrogel means, the animal, or the like. Wall 12 comprises totally,or in at least a part, a polymeric composition permeable to the passageof an external aqueous-type fluid, such as water and a biological fluid,while remaining essentially impermeable to the passage of a beneficialdrug formulation, hydrogels, and the like.

Typical materials for forming wall 12 comprise selectively semipermeablepolymers known to the art as osmosis and reverse osmosis membranes.These polymeric compositions comprise a cellulose ester, celluloseether, cellulose ester-ether, cellulose acylate, cellulose diacylate,cellulose triacylate, cellulose acetate, cellulose diacetate, cellulosetriacetate, agar acetate, amylose triacetate, beta glucan acetate,cellulose acetaldehyde dimethyl acetae, cellulose acetate ethylcarbamate, cellulose acetate methyl carbamate, cellulose acetatesuccinate, cellulose acetae dimethylaminoacetate, cellulose acetateethylcarbamate, cellulose acetate chloroacetate, cellulose dipalmate,cellulose dioctanoate, cellulose dicarpylate, cellulose dipentanlate,cellulose acetate valerate, cellulose acetate succinate, cellulosepropionate succinate, cellulose acetate p-toluene sulfonate, celluloseacetate butyrate, cross-linked selectively semipermeable polymers formedby the coprecipitation of a polyanion and a polycation as disclosed inU.S. Pat. Nos. 3,173,876; 3,276,586; 3,541,005; 3,541,006, and3,546,142; semipermeable polymers as disclosed by Loeb and Sourirajan inU.S. Pat. No. 3,133,132; pH stable, lightly cross-linked, semipermeablepolystyrene; non-mobile, cross-linked, semipermeable poly(sodium styrenesulfonate); semipermeable poly(vinylbenzyltrimethyl-ammonium chloride);cellulose acetate having a degree of substitution up to 1 and an acetylcontent up to 21%; cellulose diacetate having a degree of substitutionof 1 to 2 and an acetyl content of 21 to 35%; cellulose triacetatehaving a degree of substitution of 2 to 3 and an acetyl content of 35 to44.8%. Semipermeable polymers are known to the dispensing art in U.S.Pat. Nos. 3,845,770; 3,916,899; 4,160,020, and 4,250,108. Generally thesemipermeable compositions used for wall 12 will have a fluidpermeability of 10⁻³ to 10⁻¹ (cc mil/cm² hr/atm) expressed peratmosphere of hydrostatic or osmotic pressure difference across wall 12can be used for the intended purpose. The phrase, "non-mobile,cross-linked bond" is used in its conventional meaning to indicate thecross-linked bond is stable in the presence of acids and bases, it doesnot hydrolyze or break in these environments.

The microporous polymers used for forming wall 12, alone and incombination with a semipermeable polymer, are essentially inert, theymaintain their physical and chemical integrity during the period of drugrelease, and they can generally be described as having a sponge-likeappearance that provides supporting structure for microscopic-sizedinterconnected pores or voids. The materials can be isotropic whereinthe structure is homogenous throughout a cross-sectional area, or theycan be anisotropic wherein the structure is nonhomogeneous throughout across-sectional area. The pores can be continuous that have an openingon both faces of a microporous wall or a microporous lamina; poresinterconnected through tortuous paths of regular and irregular shapedincluding curved, curved-linear, randomly oriented continuous pores;hindered connected pores and other porous paths discernible bymicroscopic examination. Generally microporous membranes are defined bythe pore size, the number of pores, the tortuosity of the microporouspath and the porosity which relates to the size and the number of pores.The pore size of a microporous membrane is easily ascertained bymeasuring the observed pore diameter at the surface of the materialunder the electron microscope. Generally materials possessing from 5% to95% pores and having a pore size of from 10 angstroms to 100 microns canbe used for making the device. The pore size and other parameterscharacterizing the microporous structure can be obtained from flowmeasurements, where a liquid flux, J, is produced by a pressuredifference ΔP across the wall. The liquid flux through a lamina withpores of uniform radius extended through the membrane and perpendicularto its surface with area, A, is given by relation (1): ##EQU1## whereinJ is the volume transported per unit time and membrane area containing Nnumber of pores of radius r, η is the viscosity of the liquid, and ΔP isthe pressure difference across the membrane with a thickness Δx. Forthis type of membrane the number of pores N can be calculated fromrelation (2), wherein ε is the porosity defined as the ratio of voidvolume to total volume of the membrane, and A is the cross-sectionalarea of the membrane containing N pores:

    N=ε×A/πr.sup.2.                           (2)

The pore radius is calculated from relation (3): ##EQU2## wherein J isthe volume flux through the membrane per unit area produced by thepressure difference ΔP across the membrane, η, ε and Δx have the meaningdefined above and τ is the tortuosity defined as the ratio of thediffusional path length in the membrane to the membrane thickness.Relations of the above type are discussed in Transport Phenomina InMembranes by N. Lakshminatayanaiah, Chap. 6, 1969, published by AcademicPress, Inc., N.Y.

As discussed in the above named reference, p 336, Table 6.13, theporosity of the lamina having pore radius, r, can be expressed relativeto the size of the transported molecule having a radius, a, and as theratio of molecular radius to pore radius, a/r, decreases, the membranebecomes porous with respect to this molecule. That is, when the ratio,a/r is less than 0.3, the membrane becomes substantially microporous asexpressed by the osmotic reflection coefficient, σ, which decreasesbelow 0.5. Microporous membranes with a reflection coefficient, σ, inthe range of less than 1, usually from 0 to 0.5, and preferably lessthan 0.1 with respect to the active agent, are suitable for fabricatingthe system. The reflection coefficient is determined by shaping thematerial in the form of a membrane and carrying out water fluxmeasurements as a function of the hydrostatic pressure difference and asa function of the osmotic pressure difference caused by the active drug.The osmotic pressure difference creates a hydrostatic volume flux, andthe reflection coefficient is expressed by relation (4 ): ##EQU3##Properties of microporous materials are described in Science, Vol. 170,pp 1302-05, 1970; Nature, Vol. 214, p 285, 1967; Polymer Engineering andScience, Vol. 11, pp 284-388, 1971; Industrial Processing With Membranesby R. E. Lacy and Sidney Loeb, pp 131-34, 1972, published by WileyInterscience, N.Y.; and in U.S. Pat. Nos. 3,567,809 and 3,751,536.

Microporous materials having a preformed structure are commerciallyavailable and they can be made by art-known methods. The microporousmaterials can be made by etched nuclear tracking; by cooling a solutionof flowable polymer below the freezing point whereby solvent evaporatesfrom the solution in the form of crystals dispersed in the polymer andthen using the polymer followed by removing the solvent crystals; bycold or hot stretching at low or high temperatures until pores areformed; by leaching from a polymer a soluble component by an appropriatesolvent; by ion exchange reaction; and by polyelectrolyte processes.Processes for preparing microporous materials are described in SyntheticPolymer Membranes, by R. E. Kesting, Chapts. 4 and 5, 1971, published byMcGraw Hill, Inc.; Chemical Reviews, "Ultrafilter Membrane andUltrafiltration", Vol. 18, pp 373-455, 1934; Polymer Eng. and Sci., Vol.11, No. 4, pp 284-88, 1971; J. Appl. Poly. Sci., Vol. 15, pp 811-829,1971; and in U.S. Pat. Nos. 3,565,259; 2,615,024; 3,751,536; 3,801,692;3,852,224; and 3,849,528.

Microporous materials useful for making the wall include microporouspolycarbonates comprising linear polyesters of carbonic acid in whichcarbonate groups recur in the polymer chain; microporous materialsprepared by the phosgenation of a dihydroxyl aromatic such as abisphenol; microporous poly(vinylchloride); microporous polyamides suchas poly(hexamethylene adepamide); microporous modacrylic copolymersincluding those formed from poly(vinylchloride) and acrylonitrite);styrene-acrylic acid and its copolymers; porous polysulfonescharacterized by diphenylene sulfone groups in a linear chain thereof;halogenatd poly(vinylidene); polychloroethers; acetal polymers;polyesters prepared by the esterification of a dicarboxylic acid oranhydride with an alkylene polyol; poly(alkylenesulfides); phenolicpolyesters; microporous poly(saccharides); microporous poly(saccharides)having substituted and unsubstituted anhydroglucose units; asymmetricporous polymers; cross-linked olefin polymers; hydrophobic orhydrophilic microporous homopolymers; copolymers or interpolymers havinga reduced bulk density; in materials described in U. S. Pat. Nos.3,597,752; 3,643,178; 3,654,066; 3,709,774; 3,718,532; 3,803,061;3,852,224; 3,853,631, and 3,852,388; in British Patent No. 1,126,849 andin Chem. Abst., Vol. 71, 4274F, 22572F and 22573F, 1969.

Additional microporous materials include poly(urethanes); crosslinked,chain-extended poly(urethanes); microporous poly(urethanes) as in U.S.Pat. No. 3,524,753; microporous poly(imides); microporouspoly(benzimidazoles); collodion(cellulose nitrate with 11% nitrogen);regenerated proteins; semisolid, cross-linked poly(vinylpyrrolidone);microporous materials prepared by diffusion of multivalent cations intopolyelectrolyte sols as in U.S. Pat. No. 3,565,259; anisotropicpermeable microporous materials of ionically associatedpolyelectrolytes; porous polymers formed by the coprecipitation of apolycation and a polyanion as described in U.S. Pat. Nos. 3,276,589;3,541,055; 3,541,066, and 3,546,142; derivatives of poly(styrene) suchas poly(sodium styrene sulfonate) and poly(vinyl benzyltrimethylammonium chloride); the microporous materials described in U.S. Pat.Nos. 3,615,024; 3,646,178, and 3,852,224.

Further, the microporous forming materials used for the purpose of theinvention include the embodiment wherein the microporous membrane isformed in situ by a pore-former being removed by dissolving or leachingit to from the microporous wall comprising pores of controlled porosityduring the operation of the system. The pore-former can be a solid or aliquid. The term liquid, for this invention, embraces semi-solids andviscous fluids. The pore-formers can be inorganic or organic. Thepore-formers suitable for the invention include pore-formers that can beextracted without any chemical change in the polymer. The pore-formingsolids have a size of about 0.1 to 200 microns and they include alkalimetals such as sodium chloride, sodium bromide, potassium chloride,potassium sulfate, potassium phosphate, sodium benzoate, sodium acetate,sodium citrate, potassium nitrate, and the like. The alkaline earthmetal salts such as calcium phosphate, calcium nitrate, and the like.The transition metal salts such as ferric chloride, ferrous sulfate,zinc sulfate, cupris chloride, manganese fluoride, manganesefluorosilicate, and the like. The poreformers include organic compoundssuch as polysaccharides, sucrose, glucose, fructose, mannitol, lactose,sorbitol, monosaccharides, disaccharides, and the like. Also, organicaliphatic and aromatic ols, including diols and polyols as exemplifiedby polyhydric alcohols, poly(aklylene glycols), polyglycols, alkyleneglycols, poly(α-ω)-alkylenediol esters or alkylene glycols and the like.The pore formers are nontoxic, and on their removal from the wallchannels are formed through the wall that fill with fluid. The channelsbecome a path that extend from one side of the wall to the other forletting a drug formulation leave the dispensing system. In a presentlypreferred embodiment the nontoxic pore-forming agents are selected fromthe group consisting of inorganic and organic salts, carbohydrates,hydrates, poly(alkylene glycols), and glycols, and are used for formingthe wall in a biological environment.

The expression, "drug formulation", as used herein, denotes anybeneficial agent, compound or composition of matter, that can bedelivered by the dispensing device to produce a beneficial andtherapeutic results accompanied by a lessening in the incidence ofmucosal irritation frequently associated with the drug. The drugs forthe present purpose include any physiological or pharmacologicallyactive substance that produces a local or systemic effect in animals,which latter term includes warm-blooded mammals, humans and primates,household, sport and farm animals, zoo animals, fishes and reptiles. Theterm "physiologically" as used herein denotes the administration of adrug to produce normal levels and functions. The term,"pharmacologically" denotes variations in response to amounts of drugadministered to the host. Stedman's Medical Dictionary, 1966, publishedby Williams and Wilkins, Baltimore, Md. The active drug that can bedelivered include inorganic and organic drugs without limitations, drugsthat act on the central nervous system, depressants, hypnotics,sedatives, psychic energizers, tranquilizers, anticonvulsants, musclerelaxants, antiparkinson agents, analgesics, anti-inflammatories, localanesthetics, muscle contractants, antimicrobials, antimalarials,hormonal agents, contraceptives, diuretics, sympathomimetics,anti-parasitics, neoplastics, hypoglycemics, ophthalmics, electrolytes,diagnostics, cardiovascular drugs, and the like.

The drugs administrable by the dispensing device of this invention inone present embodiment embrace drugs that irritate mucosal tissues, andwhose adverse effects can be lessened, or eliminated by dispensing thedrug according to the mode and manner of the invention.

Representative of these drugs include the non-steroidalanti-inflammatory analgesic drugs. The non-steroidal anti-inflammatoryanalgesic drugs include a member selected from the group consisting ofnonsteroidal propionic acid derivatives, nonsteroidal acetic acidderivatives, nonsteroidal fenamic acid derivatives, nonsteroidalbiphenylcarboxylic acid derivatives, and nonsteroidal oxicamderivatives.

The propionic acid derivatives include a member selected from the groupconsisting of benoxaprofen, carprofen, flurbiprofen, fenoprofen,fenbufen, ibuprofen, indoprofen, ketoprofen, naproxen, miroprofen,oxaprozin, pranoprofen, pirprofen, suprofen, tiaprofenic acid,fluprofen, alminoprofen, bucloxid acid and the like. The acetic acidderivatives include a member selected from the group consisting ofalcofenac acematacin, aspirin, diclofenac, indomethacin, ibufenac,isoxepac, furofenac, fentiazac, clidanac, oxpinac, sulindac, tolmetin,zomepirac, zidometracin, tenclofenac, tiopinac, and the like. Thefenamic acid nonsteroid drugs include mefenamic acid, flufenamic acid,niflumic acid, meclofenamic acid, tolfenamic acid, and the like.Representative biphenylcarboxylic carboxylic acid nonsteroid drugsinclude diflunisol, flufenisol, and the like. Representativenonsteroidal oxicam drugs include isocicam, piroxicam, sudoxicam, andthe like. Other drugs include potassium chloride, potassium carbonate,and the like.

The dispensing device, optionally, can be used for dispensing drugs thatare difficult to dispense in a rate controlled manner because they arepoorly soluble or very soluble in aqueous fluids. These drugs can bedispensed by using the combined first and second hydrogel means of theinvention. Representative drug that are poorly soluble in water includediphenidol, meclizine hydrochloride, prochlorperazine maleate,thiethylperazine maleate, anisindone, diphenadione, erthrityltetranitrate, dizoxin, isofurophate, reserpine, acetazolamide,methazolamide, tolazamide, phenaglycodol, allopurinol, aluminum aspirin,and the like. Representative of drugs that are very soluble in waterinclude prochlorperazine edisylate, ferrous sulfate, aminocaproic acid,mecamylamine hydrochloride, bethanechol chloride, methacholine chloride,methascopolamine bromide, tridihexethyl chloride, oxprenololhydrochloride, and the like. The beneficial drugs are known to the artin Pharmaceutical Sciences, by Remington, 14th Ed., 1979, published byMack Publishing Co., Easton, Pa.; The Drug, The Nurse, The Patient,Including Current Drug Handbook, 1974-76, by Falconer et al., publishedby Saunder Company, Philadelphia, Pa.; and Medicinal Chemistry, 3rd Ed.,Vol. 1 and 2, by Burger, published by Wiley Interscience, New York.

The drug can be in various forms such as uncharged molecules, molecularcomplexes, pharmacologically acceptable salts such as hydrochloride,hydrobromide, sulfate, laurylate, palmitate, phosphate, nitrate, borate,acetate, maleate, tartrate, oleate, and salicylate. For acid drugs,salts of metals, amines, or organic cations, for example, quaternaryammonium can be used, Derivatives of drugs such as esters, ethers andamides can be used. Also, a drug that is water insoluble can be used ina form that is water soluble derivative thereof to serve as a solute,and on its release from the device is converted by enzymes, hydrolyzedby body pH, or other metabolic process, to the original biologicalactive form.

The amount of drug present in the dispensing generally is an amountsufficient for performing a therapeutic program. Generally thedispensing device will contain from 0.05 ng to 7.5 g or more, withindividual dispensing devices containing, for example, 25 ng, 1 mg, 25mg, 50 mg, 125 mg, 250 mg, 500 mg, 750 mg, 1 g, 1.5 g, and the like. Thedispensing device can be administered once, twice, thrice daily, or thelike, over a prolonger period of one day to one year, or longer. Thephrase, "drug formulation" as used for the purpose of this inventionindicates the drug is present in the compartment with at least onhydrogel means. The phrase, "drug formulation" as used for the purposeof this invention denotes the drug is present in the compartment with atleast one hydrogel means and, optionally, with at least one osmoticallyeffective solute.

Osmotically effective solutes are known also as osmagents andosmotically effective compounds. The osmagent present in the device,when used according to the mode of the invention, are osmoticallyeffective compounds soluble in fluid that enters the device, andexhibits an osmotic pressure gradient across the semipermeable wallagainst an exterior fluid. Osmotically effective osmagents useful forthe present purpose include magneisum sulfate, magnesium chloride,sodium chloride, lithium chloride, potassium sulfate, sodium carbonate,sodium sulfate, lithium sulfate, sodium sulfate, mannitol, urea,sorbitol, inositol, raffinose, sucrose, glucose, glycose, and the like.The osmagent is usually present in an excess amount, and it can be inany physical form such a particle, powder, granule and the like. Theosmotic pressure in atmospheres, ATM, of the osmagent suitable for theinvention will be greater than zero ATM, generally from zero ATM up to500 ATM, or higher. The amount of active osmagent in the compartmenthomogeneously or heterogeneously blended with the drug formulation andat least one hydrogel is usually from 0.01% to 40% , or higher. Theosmotic pressure of an osmagent is measured in a commercially availableosmometer that measures the vapor pressure difference between pure waterand the solution to be analyzed and according to standard thermodynamicprinciples the vapor pressure ratio is converted into an osmoticpressure difference. The osmometer used for the prsent measurements isidentified as Model 320B, Vapor Pressure Osmometer, manufactured byKNAUER, W. Germany and distributed by UTOPIA Instrument Col, Joliet,Ill. 60434.

The first hydrogel means and the second hydrogel carrier means suitablefor the purpose of this invention comprise hydrogels that exhibit fluidabsorbing or fluid imbibing properties. The hydrogel drug carrier meanscomprise hydrophilic, swellable polymers that interact with water andaqueous biological fluids and swell or expand to an equilibrium state.The hydrogels exhibit the ability to swell in aqueous fluids and retaina significant portion of the absorbed or imbibed fluid within thepolymer structure. The hydrogels swell or expand to a very high degree,usually exhibiting a 2 fold volume increase, usually a 2 to 50 foldvolume increase. Hydrogel compositions suitable for the present purposecomprise hydrogel compositions of plant, animal and synthetic origins.The hydrogels useful for forming the first hydrogel means are in apresently preferred embodiment neutral hydrogels. The phrase, "neutralhydrogel" as used herein denotes the hydrogel is substantially free ofan electrical charge, and it is neither acidic or basic as defined inHackh's Chemical Dictionary, 4th Ed., p 451, published in 1969 by McGrawHill Book Co., N.Y. Representative neutral hydrogels comprisepoly(hydroxyalkyl methacrylate) having a molecular weight of 20,000 to5,000,000; poly(vinylpyrrolidone) having a molecular weight of about10,000 to 360,000; poly(vinyl alcohol) having a low acetate content andlightly cross-linked with glyoxal, formaldehyde, glutaraldehyde andhaving a degree of polymerization from 200 to 30,000; poly(ethyleneoxide) having a molecular weight from 10,000 to 5,000,000; starch graftcopolymers comprising amylose and amylopectin and exhibiting a degree ofpolymerization from 200 to 10,000,000; cross-linked diester polyglucanhaving a degree of polymerization from 200 to 10,000,000; celluloseethers having a degree of polymerization from 200 to 200,000 asexemplified by methylcellulose; hydroxyalkylalkylcellulose incluidngethylhydroxyethylcellulose, hydroxybutylmethylcellulose;hydroxyethylmethylcellulose and hydroxypropylmethylcellulose; neutralpolysaccharides including nonionic compositions such as guar gum, locustbean and tamarind gum, and the like. The hydrogel polymers includinghydrophilic hydrogels prepared from hydrophilic monomers such asmonomethacrylates of polethyleneglycols and monoethers, acrylamide andmethacrylamide, N-substituted acrylamide and N-substitutedmethacrylamide, and the like.

The term "ionic" as used herein denotes a polymeric hydrogel substitutedwith at least one chemical group that can dissociate into ions or becomeelectrically charged in the presence of an aqueous type media. Hackh'sChemical Dictionary, 4th Ed., p 451, published in 1969, by McGraw-HillBook Co., N.Y. Representative of ionic hydrogels are a member selectedfrom the group consisting of anionic hydrogels, cationic hydrogels andpolyelectrolyte hydrogels. Exemplary ionic hydrogels includecarboxymethylcellulose; hydrogels formed of a copolymer of maleicanhydride with styrene, ethylene, propylene, butylene or isobutylenecross-linked with from 0.001 to about 0.5 moles of a polyunsaturatedcross-linking agent pre mole of maleic anhydride in the copolymer;hydrogels of N-vinyl lactams; acidic carboxy polymers knonw ascarboxypolymethylene and carboxyvinylpolymers, a polymer consisting ofacrylic acid cross-linked with polyallyl sucrose and sold uner thetrademark Carbopol®, acidic carboxy polymer having a molecular weight of200,000 to 6,000,000, including sodium acidic carboxyvinyl hydrogel andpotassium acidic carboxyvinyl hydrogel; Cyanamer® polyacrylamide;cross-linked indene-maleic anhydride polymers; Good-rite® polyacrylicacid polymer having a molecular weight of 60,000 to 500,000; ionicpolysaccharides such as anionic carrageenin; anionic agar; anionic gumArabic; anionic gum ghatti; and the like. Ionic hydrogels includinghydrogels prepared from acidic monomers such as acrylic acid;methacrylic acid; crotonic acid; vinyl sulfonate; phosphorylatedhydroxyalkylmethacrylates; basic monomers such asaminoalkylmethacrylate, and vinyl pyridine. The amount of a neutralhydogel means in the device is about 1% to 60% and the amount of anionic or anionic hydrogel carrier means in the device about 1% to 60%,with the total amount of both hydrogels when present about 1 to 70%,with the total amount of all ingredients present in the compartment ofthe device being 100%, such as 100 wt %. The representative polymers areknown to the art in Handbook of Common Polymers, by Scott and Roff,published by the Chemical Company, Cleveland, Ohio; ACS SymposiumSeries, No. 31, by Ratner & Hoffman, pp 1 to 36, 1976, published by theAmerican Chemcial Society; and in Recent Advances In Drug DeliverySystems, by Schacht, pp 259-78, 1984, published by Plenum Press, N.Y.

The neutral hydrogel means generally will exhibit a viscosity of 1,500centipoises to 10,000,000 centipoises when the dispensing device is inuse at body animal temperature of 35° C. to 35° C. For polyethyleneoxide with a molecular weight of 10,000 to 7,000,000, for a 2% solution,the viscosity is generally between 5 to 20,000 centipoises at a roomtemperature of 23° C.; for polyvinyl pyrrolidone with a molecular weightof between 10,000 to 500,000, for a 10% solution, the viscosity isgenerally between 5 to 5,000 centipoises at 25° C.; forhydroxypropylmethylcellulose having a molecular wieght of between 1,000to 200,000, a 2% solution in an aqueous media, the viscosity is from 10centipoises to 2,000,000 centipoises. The ionic or anionic hydrogelcarrier means in the device in the presence of a drug formulation and aneutral hydrogel will exhibit a viscosity up to 2,500 centipoises, andon its release from the device in the presence of fluid in an animalhost, the viscosity will be greater than 2,500 centipoises. Theviscosity of a drug solution, or the viscosity of a drug-viscosityhydrogel inducing solution is ascertained by conventional measurement.The viscosity of a solution can be measured with Wells-BrookfieldViscometer Model LVT, or with a Brookfield Viscometer. Methods andapparatus for measuring viscosity are known in Pharmaceutical Science,by Remington, 14th Ed., pp 359-71, 1970, published by Mack PublishingCo., Easton, Pa.

The presence or the absence of irritation can be ascertained with knowntests. One test for irritation consists in using rabbits that have beenanesthetized, exposing the colon through a mid-life abdominal incision,having a segment distal to the caecum isolated by placing two ligatures15 to 20 cm apart around the colon. The isolated segment is continuouslysupplied by its blood vessels and nerves. The isolated segment isclamped in a multi-chambered cell and each cell perfused with artificalintestinal fluid at 37° C. Delivery device dispensing a drug are placedin the cells directly into contact with the mucosa for a period of atleast six hours. Tissue irritation in response to the test formulationwas ascertained at the end of the tract, leading to an irritation index.Procedures for measuring irritation are known in J. Pharm. Sci., Vol.60, No. 9, pp 1314-1316, 1971; Arzneim-Forsch Drug Res., Vol. 23, No.12, pp 1709-12, 1973; and in Laryngoscope, Vol. 93, pp 184-87, 1983.

The device of the invention is manufactured by standard techniques. Forexample, in one manufacture, the drug and other ingredients that may behoused in one area of the compartment adjacent to an exit passageway arepressed into a solid possessing dimensions that correspond to theinternal dimensions of the area of the compartment the drug will occupy,or the drug and other ingredients and a solvent are mixed into a solidor semisolid form by conventional methods such as ballmilling,calendering, stirring, or rollmilling, and then pressed into apreselected shape. Next, a wall is applied around thecompartment-forming, pressed reservoir drug hydrogel mass. The wall canbe applied by molding, spraying or dipping the pressed shapes into awall forming material. Another and presently preferred technique thatcan be used for applying the wall is the air suspension procedure. Thisprocedure consists in suspending and tumbling the pressed drug hydrogelcomposition in a current of air and a wall forming composition until thewall is applied around the drug hydrogel composite. The air suspensionprocedure is described in U.S. Pat. No. 2,779,241; in J. Am. Pharm.Assoc., Vol. 48, pp 451-59, 1979; J. Am. Pharm. Assoc., Vol. 49, pp82-84, 1960. Other standard manufacturing procedures are described inModern Plastics Encyclopedia, Vol. 46, pp 62-70, 1969; and inPharmaceutical Sciences, by Remingotn, 14th Ed., pp 1626-78, 1970,published by Mack Publishing Co., Easton, Pa.

Exemplary solvents suitable for manufacturing the wall include inorganicand organic solvents that do not adversely harm the wall formingmaterials, and the final device. The solvents broadly include membersselected from the group consisting of aqueous solvents, alcohols,ketones, esters, ethers, aliphatic hydrocarbons, halogenated solvents,cycloaliphatic, aromatics, heterocyclic solvents, and mixtures thereof.Typical solvents include acetone, diacetone, alcohol, methanol, ethanol,isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate,isopropyl acetate, n-butyl acetate, methyl isopropyl ketone,methylpropyl ketone, n-hexane, n-heptane, ethylene glycol monoethyleither, ethylene glocol monoethyl acetate, methylene dichloride,ethylene dichloride, propylene dichloride, carbon tetrachloride,nitroethane, nitropropane, tetrachloroethane, ethyl ether, isopropylether, cyclohexane, cyclo-octane, benzene, toluene, naphtha,1,4-dioxane, tetrahydrofuran, dglyme, water, and mixtures thereof suchas acetone and ethyl alcohol, methylene dichloride and methanol,ethylene dichloride and methanol, and the like.

The expression "exit means" as used herein comprises means and methodssuitable for relasing a beneficial drug from the dispensing device. Themeans include at least one passageway or orifice that passes through thewall for communicating with the drug in the compartment. The expression,"at least one passageway" includes aperature, orifice, bore, pore,porous element through which a beneficial drug can migrate, a hollowfiber, capillary tube, and the like. The expression also includes amaterial that erodes or is leached from the wall in the fluidenvironment of use to produce at least one passageway in the device.Representative materials suitable for forming at least one passageway,or a multiplicity of passageways, include an erodible poly(glycolic) orpoly(lactic) acid member in the wall, gelatinous filaments, poly(vinylalcohol), leachable materials such as fluid removable pore formerpolysaccharide salt, oxide polysaccharide, salt, oxide and the like. Apassageway or a plurality of passageways can be formed by leaching amaterial such as sorbitol from the wall. The passageway can have anyshape. For example, round, triangular, square, elliptical, irregular,and the like. Also, the device can be constructed with one or morepassageways. In an embodiment, when the device is fabricated with morethan one passageway, the passageway can be construed as the functionalequivalent in an operative embodiment of a single osmotic passageway.The expression, "osmotic passageway" includes passageways formed bymechanical drilling, laser drilling, eroding or leaching a passagewaythrough the wall. Generally, for the purpose of this invention, anosmotic passageway will have a maximum cross-sectional area, A_(max),defined by relation (5): ##EQU4## wherein L is the length of thepassageway, (M/t) is the mass delivery rate of the agent released perunit of time, D is the diffusion coefficient of the medicine in therelease solution, S is the solubility of the medicine in the fluid and Fhas a value of approximately 2 to 1000, said osmotic passageway having aminimum area, A_(min), defined by relation (6): ##EQU5## wherein L isthe length of the passageway, v/t is the volume of the medicine releasedper unt of time, π is 3.14, η is the viscosity of the solution beingreleased, and ΔP is the hydrostatic pressure difference between theinside and the outside of the compartment and having a value up to 20ATM. The dimension for the osmotic passageway is disclosed in U.S. Pat.No. 3,916,899. Laser drilling equipment having photo detection means fororienting a device for surface selected drilling is known in U.S. Pat.Nos. 4,063,064; 4,088,864, and by leaching in U.S. Pat. No. 4,200,098.

DESCRIPTION OF EXAMPLES OF THE INVENTION

The following examples are merely illustrative of the present inventionand they should not be considered as limiting the scope of the inventionin any way, as these examples and other equivalents thereof will becomeapparent to those versed in the art in the light of the presentdisclosure, the drawings and the accompanying claims.

EXAMPLE 1

A drug dispensing device is manufactured for dispensing the beneficialdrug potassium chloride to a gastrointestinal tract as follows: first, acompartment forming composition comprising, in weight percent, 92.25%potassium chloride powder, 5% potassium carboxypolymethylene, 2%polyethylene oxide having a molecular weight of about 5,000,000, and0.5% silicon dioxide are mixed together. Next, the mixture is passedthrough a 40 mesh stainless steel screen and then dry blended in aV-blender for 30 minutes to produce a uniform blend. Next, 0.25%magnesium stearate is passed through an 80 mesh stainless steel screen,and the blend given an additional 5 to 8 minutes blend.

Then, the homogeneously dry blender powder is placed into a hopper andfed to a compartment forming press, and known amounts of the blendcompressed into 5/8 inch oval shaped designed for oral use. The ovalshaped precompartments are coated next in an Accela-Cota® wall formingcoater with a wall formign composition comprising 91% cellulose acetatehaving an acetyl content of 39.8% and 9% polyethylene glycol 3350. Aftercoating, the wall coated drug compartments are removed from the coaterand transferred to a drying oven for removing the residual organicsolvent used during the wall forming procedure. Next, the coated devicesare transferred to a 50° C. forced air oven for drying about 12 hours.Then, passageways are formed in the wall of the device using a laser fordrilling two passageways on the major axis of each face of thedispensing device.

EXAMPLES 2-6

The procedure of Example 1 is repeated in the following examples withall manufacturing procedures as described for providing the followingdispensing devices:

2. A dispensing device comprising a compartment weighing 824.18 mgcomprising 91% powdered potassium chloride, 5% potassiumcarboxypolymethylene, 3% polyethylene oxide coagulant, 0.5% magnesiumstearate, and 0.5% silica, a wall weighing 38.50 mg comprising 91%cellulose acetate 39.8% acetyl and 9% polyethylene glycol 3350. Thedevice had 2 passageways with a diameter of 0.51 mm. The device has anaverage release rate of 29 mg per hour and a cumulative amount releasedof 710 mg in 24 hours.

3. A dispensing device comprising a compartment weighing 814.22 mgcomprising 92% powdered potassium chloride, 5% potassiumcarboxypolymethylene, 2% polyethylene oxide having a molecular weight of5,000,000, 0.5% magnesium stearate, 0.5% silica, a wall weighing 39.30mg comprising 91% cellulose acetate having an acetyl content of 39.8%and 9.0% polyethylene glycol. The device has two passageways with adiameter of 0.5 mm. The device exhibits an average release rate of 30 mgper hour for 24 hours with a cumulative amount released of 718.8 mgs.

4. A dispensing device comprising a compartment weighing 838 mgcomprising 89.5% potassium chloride powder, 7.2% potassium carboxyvinylpolymer, 2.8% polyethylene oxide coagulant having a molecular weight of5,000,000, 0.25% silica and 0.25% magnesium stearate, and a wallweighing 21.03 mg comprising 97% cellulose acetate 39.8% and 3%polyethylene glycol. The device had two passageways with a diameter of0.51 mm. The device had an average release rate of 29 mg per hour for 24hours and a cumulative amount released of 698 mgs.

5. A dispensing device comprising a compartment weighing 872 mgcomprising 86% potassium chloride, 10% sodium Carbopol 934 P acarboxyvinyl polymer of acrylic acid crosslinked with polyallyl ether ofsucrose having an average of about 5.8 allyl groups for each molecule ofsucrose, and 4% Polyox® coagulant a hydrophilic polymer of polyethyleneoxide having a molecular weight of about 5,000,000, and a wall having aweight of 18.6 mg comprising 97% cellulose acetate 39.8 and 3%polyethylene glycol 4000. The device had two passageways with a diameterof 0.508 mm. The device had an average rate of release of 29.7 mg perhour and a cumulative amount release of 716 mg in 24 hours.

6. A dispensing device comprising a compartment weighing 872 mgcomprising 86% potassium chloride, 10% methoxycellulose and 4% Polyox®coagulant, and a wall weighing 18.5 mg comprising 95% cellulose acetate39.8% and 5% polyethylene glycol 4000. The dispenser at two passagewayswith a diameter of 0.51 mm. The device had an average of release of 30.5mg per hour and a cumulative amount released of 731.4 mg over anextended period of 24 hours.

EXAMPLE 7

An osmotic therapeutic device for the controlled and the continuous oraldelivery of the beneficial drug potassium chloride is prepared accordingto the above procedure. The device of this example comprises acompartment containing potassium chloride powder 750 mg, potassiumCarbomer® 40.65 mg, a potassium carboxypolymethylene hydrogel with amolecular weight of about 300,000, polyethylene oxide coagulant 16.3 mg,a hydrogel having a molecular weight of about 5,000,000, silicon dioxide4 mg and magnesium stearate 2 mg. The device comprises a 4 mil thickwall of cellulose acetate 91% and polyethylene glycol 9%. The devicecomprises 4 passageways of 20 mil diameter and exhibited a t90 to 20hrs. The device collapses at the end of the drug delivery period therebyenhancing passage of the device from the gastrointestinal tract. Thedevice collapses under a pressure of 40 mm Hg to 270 mm Hg. The devicecollapses when the external pressure exerted against the device exceedsboth the resistance exerted by the wall of the device and the resistancegenerated by viscous flow of the drug gel composition hydrodynamicallypumped through the passageway of the device. Hence, the collapsepressure P_(c) is expressed as two components:

    P.sub.c =P.sub.h +P.sub.g                                  (7)

wherein P_(h) is the pressure required to collapse the empty device andP_(G) is the pressure required to deliver the contents of the devicefrom the device. The factor P_(h) can further be expressed as equation(8):

    P.sub.h ≅0.8(Eh.sup.2 /R.sup.2)                  (8)

where E is Young's moduls of the wall, h is the thickness of the walland R is the maximum radius of curvature of the device. The pressurerequired to deliver a viscous drug gel composition through thepassageway, P_(G), is composed of two pressure terms as expressed byequation (9):

    P.sub.G =ΔP.sub.entrance +ΔP.sub.capillary     (9)

where ΔP_(entrance) is the pressure drop of the viscous compositionentering the passageway and ΔP_(capillary) is the pressure drop of thecomposition flowing through the passageway. According to Poiseuille law,the laminar viscous flow through a capillary is expressed by equation(10):

    ΔP.sub.capillary =ηQ (8h/πr.sup.4)            (10)

where η is the viscosity of the composition inside the device, h is thethickness of the wall, r is the radius of the passageway, and Q is thevolume flow rate through the passageway. For a small Reynold's number,the entrance effect can be approximated by a tube length of L equal to 2r, as expressed by equation (11):

    P.sub.G =ηQ (8/π.sub.r.sup.4) (h+2r)                (11)

Substituting (8) and (11) into (7) results in equation (12): ##EQU6##Thus, for a device comprising potassium chloride the collapse pressureis calculated as follows: E=1.4(10)⁵ psi for a cellulose acetate wallhaving a thickness h of 1.7 mil and R of 0.5 inch, (about 13 mm), theP_(h) is given by equation (13) and (14): ##EQU7##

    P.sub.h =1.3 psi=67 mm H.sub.g                             (14)

Therefore, from equation (12), the P_(c) is as follows (15):

    P.sub.c 32 67+ηQ(8/πr.sup.4)(h+2r)                  (15)

where r=10 mil, (0.026 cm), Q=0.43 ml/min assuming all the contents arecompressed out in about 1 min, η is the viscosity of the core solutionas set forth in FIG. 15, for a final P_(c) equal to 67+0.0043 n for thedevice, having 4 passageways for delivering the drug over time.

EXAMPLE 8

An osmotic therapeutic device for the controlled and continuous deliveryof indomethacin sodium trihydrate orally to the gastrointestinal tractis prepared as follows: a drug composition is prepared for housing inthe compartment of the device by thoroughly blending 325 mg of sodiumindomethacin trihydrate, 100 mg of sodium carboxypolymethylene, 25 mg ofmethoxycellulose, 25 mg of polyethylene oxide, 3 mg silica and 2 mg ofmagnesium stearate and then prssed in a Manesty press with a 7/16 inchpunch using a pressure head of 11/2 tons to produce the drug hydrogelcomposition.

Next, a semiperemable wall is formed by blending 170 g of celluloseacetate having an acetyl content of 39.8 with 2325 ml of methylenechloride and 1992 mil of methanol, and spray coating the drug hydrogelcomposition in an air suspension machine unitl 2.1 ml thicksemipermeable wall surrounds the compartment. The coated device is driedfor 72 hours at 50° C., and then three 15 mil (0.34 mm) passageways arelaser drilled through the wall for releasing the beneficial drug over anextended period of time.

EXAMPLE 9

A device is manufactured in the form of an oral delivery device fordelivering the beneficial analgesic sodium salicylate to thegastrointestinal tract is manufactured as follows: first a compositioncomprising 325 mg sodium salicylate 18 mg of sodiumcarboxypolymethylene, 11 mg of polyacrylamide, 10 mg of magnesiumstearate and 10 mg of silica is prepared by blending the ingredientsinto a homogenous blend and then pressing the blend into a solid mass.The blend is compressed in a Manesty tableting machine set to a Stoke'shardness of 8 kg. Next, the compressed mass is coated by dippingapproximately one-half of the device into a wall forming compositioncomprising 45% by weight of cellulose acetate having an acetyl contentof 39.8%, 45% by weight of sorbitol and 10% by weight of polyethyleneglycol. The coating is applied from a coating composition comprisingmethylene chloride-methanol-water, 62:35:3 by weight. The sorbitol isleached from the wall during operation to form in situ passageways ofcontrolled release porosity. Next, the remainder of the composition iscoated with a semipermeable wall forming composition by dipping theprevously uncoated area into a composition comprising 50% by weight ofcellulose acetate having an acetyl content of 39.8% and 50% by weight ofcellulose acetate having an acetyl content of 32%. The latter wallforming composition is applied from a solvent consisting of methylenechloride and methanol 80:20 by weight. The device delivers the drugthrough the in situ passageways as a controlled rate over time.

EXAMPLE 10

The procedure described in Example 9 is repeated with all the conditionsas set forth, except that in this example the beneficial drug is thesodium salt of naproxen.

The present invention's unexpected ability to lessen unwanted sideeffects associated with the administration of many drugs is demonstratedby using the irritation test. This test, mentioned above, demonstratesthe effect of drug contact on mucosal tissue. The test measures theirritation area in cm² the irritation score, and the irritation index.The unexpected result indicates a lessening of the incidence ofirritation is evident from a low irritation index. A comparison of theeffects of the drug potassium chloride administered by variousprocedures is set forth below. An osmotic device administering potassiumchloride free of hydrogel exhibited an irritation area of 6.7 cm², anirritation score of 3.5 and irritatio index of 23.5. Potassium chlorideadministered by leaching from a microporous polymer exhibited anirritation area of 4.1 cm², an irritation score of 3.5 and an irritationindex of 14.4. An osmotic device administering a composition comprisingpotassium chloride and 30% polyethylene oxide having a molecular weightof 600,000 exhibited an irritation area of 4.0 cm, an irritation scoreof 3.5 and an irritation index of 14.1. An osmotic device administeringa composition comprising potassium chloride and 30% starch graft polymerexhibited an irritation area of 3.2 cm², an irritation score of 3.5 andan irritation index of 11.0.An osmotic device administering acomposition comprising potassium and 30% carboxyvinyl polymer having amolecular weight of 200,000 exhibited an irritation area of 2.0 cm², anirritation score of 3.3 and an irritation index of 6.6. An osmoticdevice administering a composition comprising potassium chloride, 5%potassium carboxypolymethylene having a molecular weight of 3,000,000and 2% polyethylene oxide having a molecular weight of 5,000,000exhibited an irritation area of 0.4 cm², an irritation score of 1 and anirritation index less than 1. The osmotic Device used in the test had at₉₀ of 12 hrs and a delivery rate of 45 mg/hr for potassium chloride.

In summary, it will be greatly appreciated that the present inventioncontributes to the art an unobvious drug delivery device possessing wideand practical application. While the invention has been described andpointed out in detail and with reference to operative embodimentsthereof, it will be understood that those skilled in the art willappreciate that various changes, modifications, substitutions andomissions can be made without departing from the spirit of theinvention. It is intended, therefore, that the invention embrace thoseequivalents within the scope of the claims which follow.

We claim:
 1. A dosage form for delivering a beneficial drug to a fluidbiological environment for use, the dosage form comprising:(a) a wallcomprising in at least a part a semipermeable composition permeable tothe passage of fluid and substantially impermeable to the passage ofdrug, which wall surrounds and forms; (b) a compartment housing acomposition comprising (1) a therapeutically effective dose of thebeneficial drug potassium chloride blended with (2) means for aiding indelivering the potassium chloride from the compartment and for lesseningthe incidence of unwanted side effects of potassium chloride on thebioloical environment of use, said means comprising a first hydrogel anda different second hydrogel; (c) at least one passageway in the wallcommunicating with the compartment and the exterior of the dosage formfor delivering the composition comprising the potassium chloride and themeans from the dosage form over a prolonged period of time; and, (d)wherein, when the dosage form is in operation in the environment of use,the dosage form delivers the composition comprising the potassiumchloride and the means comprising the first and second hydrogels for thepotassium chloride therapeutic effects and for simultaneously lesseningthe incidence of unwatned side effects on the environment of use.
 2. Adosage form for delivering the beneficial drug potassium chloride to ananimal, the dosage form comprising:(a) a wall comprising celluloseacetate and polyethylene glycol which wall is permeable to the passageof fluid and substantially impermeable to the passage of potassiumchloride, which wall surrounds and forms; (b) a compartment containing acomposition comprising (1) a therapeutically effective amount ofpotassium chloride, (2) potassium carboxypolymethylene and (3)polyethylene oxide; (c) at least one passageway in the wallcommunicating with the compartment and the exterior of the dosage formfor delivering the composition comprising potassium chloride, potassiumcarboxypolymethylene and polyethylene oxide to the animal over aprolonged period of time; and, (d) wherein, when the dosage form is inoperation in the animal it delivers the composition comprising potassiumchloride for its beneficial effects and, concomitantly, potassiumcarboypolymethylene and polyethylene oxide for lessening the incidenceof irritation of mucosal tissue of the animal.
 3. The dosage form fordelivering the benefical drug potassium chloride according to claim 1,wherein the passageway is a pore and the dosage form comprises from 50mg to 750 mg of potassium chloride.
 4. The dosage form for deliveringthe beneficial drug potassium chloride according to claims 1, whereinthe passageway is a pore, the wall comprises lactose, and the dosageform delivers potassium chloride for reversing potassium depletion. 5.The dosage form for delivering the beneficial drug potassium chlorideaccording to claim 1, wherein the passageway is a pore, the wallcomprises sorbitol, and the dosage form delivers potassium chloride foraiding in maintaining the potassium requirement of the animal.